Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition

NCT03533179 | Completed Phase 4

• 1 other identifier: Glucagon+Beta-blocker
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This trial investigates effects of a glucagon bolus injection on heart rate, blood pressure and cardiac output during beta-blocker-induced cardiodepression. Furthermore, the effects of two different doses of intravenous glucagon on hemodynamic parameters are explored.

Conditions

Drug Overdose; Overdose of Beta-adrenergic Blocking Drug

Keywords

Glucagon; Beta-adrenergic antagonist; poisoning

Outcome Measures

Primary Outcomes (1)

• Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average)

  Arterial catheter connected to a pressure transducer records heart rate (beats per minute).

  Glucagon bolus + 5±1 minute

Secondary Outcomes (6)

• Change in heart rate from baseline compared between study days.

  -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes

• Change in stroke volume (ml) from baseline compared between study days.

  -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes

• Change in systolic, diastolic and mean arterial pressure (mmHg) from baseline compared between study days.

  -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes

• Glucagon pharmacokinetics

  Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes

• Effects of glucagon on blood glucose compared to placebo

  Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes

Other Outcomes (3)

• Effects of glucagon compared to placebo on gastric emptying time

  Baseline and glucagon +10, +20, +30, +40, +50, +60 minutes

• Effects of glucagon compared to placebo on norepinephrine levels

  T-20, T0, glucagon+5, +30, +60 minutes

• Cardiac conductivity compared between days with glucagon1 and corresponding placebo days.

  Baseline and glucagon +5, +10, +20, +30, +40, +50, +60 minutes

Study Arms (5)

Esmolol-placebo+glucagon 1 placebo (A)

EXPERIMENTAL

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. \+ Physiologic saline - glucagon dummy bolus 50 ml at time=0.

Drug: Physiologic saline - glucagon dummy; Drug: Physiologic saline - esmolol dummy

Esmolol+glucagon 1 placebo (B)

EXPERIMENTAL

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. \+ Physiologic saline - glucagon dummy bolus (50 ml) at time=0.

Drug: Esmolol; Drug: Physiologic saline - glucagon dummy

Esmolol+glucagon 1 (C)

EXPERIMENTAL

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes. +Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)

Drug: Glucagon; Drug: Esmolol

Esmolol-placebo+glucagon 2 (D)

EXPERIMENTAL

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. +Glukagon 2 (50 μg/kg bolus - over 30 min in 50 ml isotonic fluid from time=0 min)

Drug: Glucagon; Drug: Physiologic saline - esmolol dummy

Esmolol-placebo+glucagon 1 (E)

EXPERIMENTAL

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes. \+ Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)

Drug: Glucagon; Drug: Physiologic saline - esmolol dummy

Interventions

Glucagon DRUG

Glucagon 1 mg/ml solution is dissolved in 50 ml isotonic fluid and injected as bolus corresponding to 50 micrograms/kg over 1-3 minutes from time=0 on day C+E. on day D ("glucagon 2"), 50 micrograms/kg of glucagon is infused over 30 minutes from time=0 to time =30.

Also known as: GlucaGen, ATC H04AA01

Esmolol+glucagon 1 (C); Esmolol-placebo+glucagon 1 (E); Esmolol-placebo+glucagon 2 (D)

Esmolol DRUG

Esmolol hydrochloride 10 mg/ml is infused from time -15 min to time + 30 minutes as an initial bolus followed by an infusion. infusion rate is tapered if heart rate declines below 30 beats per minute (bpm) or \>25 % from baseline, systolic blood pressure decreases below 80 mmHg or the participant experiences side effects.

Also known as: Brevibloc, ATC C07AB09

Esmolol+glucagon 1 (C); Esmolol+glucagon 1 placebo (B)

Physiologic saline - glucagon dummy DRUG

Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.

Also known as: normal saline

Esmolol+glucagon 1 placebo (B); Esmolol-placebo+glucagon 1 placebo (A)

Physiologic saline - esmolol dummy DRUG

Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.

Also known as: normal saline

Esmolol-placebo+glucagon 1 (E); Esmolol-placebo+glucagon 1 placebo (A); Esmolol-placebo+glucagon 2 (D)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Gender Eligibility Details: Male volunteers, determined healthy by medical history, physical examination including laboratory results
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male determined by investigator, based upon physical examination, medical history, ECG, vital signs and laboratory results
• Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 and body weight between 50 and 100 kg, inclusive, at screening visit.

You may not qualify if:

• Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
• Bradycardia (\<45 beats per minute)
• Hypotension (systolic blood pressure \< 100 mmHg)
• Second or third degree atrioventricular conduction delay
• Sick sinus syndrome
• Any heart disease or hypertension
• Pheochromocytoma
• Allergy to any active or inactive ingredient contained in investigatory medicines or tools.
• Raynaud's syndrome
• Prinzmetal's angina
• Diabetes
• Pulmonary disease
• Pheochromocytoma
• Any contraindication against investigatory medicines or tools.

Sponsors & Collaborators

• University Hospital Bispebjerg and Frederiksberg: lead

Study Sites (1)

University Hospital Bispebjerg

Copenhagen, Denmark

Location

Related Publications (11)

• Brubacher JR. 62. β-adrenergic antagonists. In: Hoffman RS, Howland MA, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies. New York: : McGraw-Hill Education 2015. 856-69.

  BACKGROUND

• Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar;81(3):453-61. doi: 10.1111/bcp.12763. Epub 2015 Oct 30.

  PMID: 26344579 BACKGROUND

• Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41(5):595-602. doi: 10.1081/clt-120023761.

  PMID: 14514004 BACKGROUND

• Beta blocker poisoning - UpToDate. https://www.uptodate.com/contents/beta-blocker-poisoning? search=beta%20blocker%20overdose&source=search_result&selectedTitle=1~14&usage_type=default&display_rank=1 (accessed 14 Feb 2018).

  BACKGROUND

• Parmley WW, Glick G, Sonnenblick EH. Cardiovascular effects of glucagon in man. N Engl J Med. 1968 Jul 4;279(1):12-7. doi: 10.1056/NEJM196807042790103. No abstract available.

  PMID: 4872564 BACKGROUND

• Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995 Nov;48(5):849-54.

  PMID: 7476915 BACKGROUND

• Rodgers RL. Glucagon and cyclic AMP: time to turn the page? Curr Diabetes Rev. 2012 Sep;8(5):362-81. doi: 10.2174/157339912802083540.

  PMID: 22587514 BACKGROUND

• St-Onge M, Dube PA, Gosselin S, Guimont C, Godwin J, Archambault PM, Chauny JM, Frenette AJ, Darveau M, Le Sage N, Poitras J, Provencher J, Juurlink DN, Blais R. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila). 2014 Nov;52(9):926-44. doi: 10.3109/15563650.2014.965827. Epub 2014 Oct 6.

  PMID: 25283255 BACKGROUND

• Reilly CS, Wood M, Koshakji RP, Wood AJ. Ultra-short-acting beta-blockade: a comparison with conventional beta-blockade. Clin Pharmacol Ther. 1985 Nov;38(5):579-85. doi: 10.1038/clpt.1985.227.

  PMID: 2865029 BACKGROUND

• Medhus AW, Lofthus CM, Bredesen J, Husebye E. Gastric emptying: the validity of the paracetamol absorption test adjusted for individual pharmacokinetics. Neurogastroenterol Motil. 2001 Jun;13(3):179-85. doi: 10.1046/j.1365-2982.2001.00249.x.

  PMID: 11437980 BACKGROUND

• Petersen KM, Bogevig S, Riis T, Andersson NW, Dalhoff KP, Holst JJ, Knop FK, Faber J, Petersen TS, Christensen MB. High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial. J Am Heart Assoc. 2020 Nov 3;9(21):e016828. doi: 10.1161/JAHA.120.016828. Epub 2020 Oct 26.

  PMID: 33103603 DERIVED

MeSH Terms

Conditions

Drug Overdose; Poisoning

Interventions

Glucagon; Glucagon-Like Peptide 1; esmolol; Saline Solution

Condition Hierarchy (Ancestors)

Prescription Drug Misuse; Drug Misuse; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Proglucagon; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Glucagon-Like Peptides; Gastrointestinal Hormones; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Kasper M Petersen, MD

  University Hospital Bispebjerg and Frederiksberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Interventions will be administered behind a curtain covering half the participant and thus the arm in which intervensions are administered. A list allocating participants to interventions are kept in an opaque envelope in a locked cabinet at the trial site. Outcome assessor will not have access to this list.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Model Details: 5-arm, participant and outcome-assessor blinded, randomized, placebo-controlled study.

Study Record Dates

• First Submitted: March 9, 2018
• First Posted: May 23, 2018
• Study Start: June 1, 2018
• Primary Completion: October 1, 2019
• Study Completion: October 1, 2019
• Last Updated: October 17, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)